Mammals have evolved a defensive surveillance mechanism, known as the immune system, which protects them from a wide variety of environmental agents such as pathogenic microorganisms (e.g., viruses, bacteria and parasites). The immune system can specifically recognize, immobilize and eliminate environmental agents by way of a cellular-based or immunoglobulin-based response. However, certain human diseases are caused by either an over-reaction or under-reaction of the immune system. Such inappropriate or inopportune immune responses can lead to immunodeficiencies and can lead to autoimmune diseases.
When the immune system recognizes environmental agents as foreign, an undesirable immunopathological disorder can result (hypersensitivity disease), commonly referred to as an allergic reaction. Allergies in man are characterized by the appearance in serum and tissue of immunoglobulins of the immunoglobulin E (IgE) isotype directed against specific environmental agents. More formally, diseases in which the predominant cause can be attributed to the degranulation of tissue mast cells, stimulated by the cross-linking of the IgE receptor by antigen-bound immunoglobulins of the IgE isotype, are classified as atopic disorders (Atopy). Antigen crosslinking of surface-bound IgE molecules leads to an immediate degranulation of the mast cells and release of pre-formed inflammatory mediators, such as histamine and proteolytic enzymes, and subsequent synthesis and secretion of other arachidonic acid metabolites, such as platelet activating factor and leukotrienes, which act as chemoattractants, inflammatory activators and spasmogens for the tissue surrounding the site of allergen exposure (J. Morley et al., Mediators of Allergy. In Allergy: Immunological and Clinical Aspects, M. H. Lessof, ed. John Wiley & Sons; Chichester, England: 45-72 (1984)). This combination of pharmacological mediators (whose activities also include vasodilation and bronchoconstriction) leads to irritability in nasal passageways resulting in sneezing, running noses, congestion, headaches and watery eyes, all of which are well known symptoms of allergic rhinitis (a sub-class of the disorders collectively called atopy). Atopy includes allergic rhinitis, asthma, food allergies, drug allergies, atopic dermatitis, hyper IgE syndrome and anaphylaxis (M. H. Lessof et al. Gastrointestinal reactions and food intolerance. In Allergy: Immunological and Clinical Aspects, M. H. Lessof, ed. John Wiley & Sons; Chichester, England 175-218 (1984)). Atopic disorders and similar undesirable immune effects resulting from allergic type reactions cause tissue damage and life threatening conditions.
It is estimated that twenty percent of the North American populations and Western European populations is effected by allergies and asthma alone. Therefore, suppression of undesirable immune effects, such as those associated with the IgE isotype, is paramount to treating patients suffering from various immune related disorders. Current methods for treating patients with immune related disorders are non-specific (i.e., destroy both the desirable and undesirable effects of the immune response) and include dangerous side effects.
Current therapy in allergy is generally divided into three categories. The first category of therapy is directed toward preventing the action of inflammatory mediators, by symptomatic treatment via anti-histamines, systemic bronchodilators, aerosol bronchodilators, systemic corticosteroids, and nasal steroids. The second category of therapy is directed toward generalized immuno suppression with the use of topical or systemic corticosteroids. The third category of therapy is directed toward prophylactic desensitization (by repeated injection of impure allergen mixtures) directed toward the stimulation of blocking antibodies (most likely IgG) to neutralize or compete with an IgE response. None of these therapies are specific.
What is needed is a therapy that is specific (i.e., does not interfere with desirable functions of the immune response but hinders the life threatening or tissue damaging aspects of the immune response) for treating undesired immunologic effects. Such an immunosuppressive treatment would benefit patients suffering from the effects of autoimmunity, and hypersensitivity.
Immunosuppressive effects of prostaglandins in vitro has been demonstrated with natural prostaglandin E2 (PGE.sub.2) (See J. Pene et al., Proc. Natl. Acad. Sci. USA. 85: 6880 (1988)). In addition, certain prostaglandins have been disclosed as useful for the treatment of skin diseases such as psoriasis, useful for the prevention of thrombus formation, and useful for stimulating the production of growth hormone and as regulators of the immune response (see U.S. Pat. Nos. 4,155,908 and 4,128,564). Likewise, U.S. Pat. Nos. 4,260,771 and 4,059,587 disclose compounds with prostaglandin-like biological activity that are useful as renal vasodilators, as platelet aggregation inhibitors, and as treatments of certain autoimmune diseases. None of the disclosures, however, teach a method of inhibiting production of IgE.
The present invention provides a highly specific method for treating undesirable effects of the immune response associated with the production of IgE. The method is highly specific in that the method inhibits the IgE response without inhibiting the response of other isotypes.